(Abbreviations: LW, Lung Weight; LBWR, Lung to Body weight ratio; DA, Ductus Arteriosus; RV, right ventricle; TV, tricuspid valve; PA, Pulmonary valve; LV, Left ventricle)

4.DISCUSSION

4.1. The severity of pulmonary hypoplasia in CDH is inconsistent.

Pulmonary hypoplasia is diagnosed by decreased lung growth and immature in CDH. It is based on measurement of lung-to-body weight ratio(LBWR) <0.012 (>28 weeks)², and the pathological characteristics are reduced lung parenchyma and terminal branches of bronchioles, acinar hypoplasia ². Gas exchange is impaired severely due to the reduction of alveolar cavity area and thickening of alveolar walls and mesenchyme¹¹. Changes in cell phenotype, cell proliferation, and abnormalities in intercellular signaling pathways have been identified as potential pathogenic causes in various animal models of CDH¹². In this study, LBWR was lower than 0.012, meanwhile a part of postmortem examination identified lung development of CDH stagnating at an earlier developmental stage and presented in the pseudo-glandular or canalicular period, which is consistent with the clinical GA in diagnosis.

The important finding was that histological manifestations of the lung were not consistent. The lung development was observed with a relatively normal performance in ipsilateral lungs or bilateral. Current research considers the occurrence of CDH to be a dual-hit hypothesis¹³. This theory holds that the aberrant lung developments exist before the diaphragmatic defect occurs, and the compression secondary to abdominal viscera herniations into the thorax results inhibition of growth and maturation further. Though this study has not fully verified this hypothesis. The hit only occurred in the compression secondary to abdominal viscera herniations, so pulmonary histological development was close to the normal structure. The pathogenesis of CDH is complex in person, and the inconsistency reflects that CDH is a severe disease with strong heterogeneity and evaluating lung development of infants may provide clearer guidance on the management of ventilator settings. Given the low sample size present in this study, we lack statistical significance of predictors for lung hypoplasia.

It was worth noting that in 7 of the 8 cases received HFOV early after birth, which was thought to produce less pulmonary barotrauma¹⁴. And because of the continuous instability of the physiological state, the ventilator support parameters were adjusted, and the mean MAP increased from 14 to 18 cmH₂O. Based on the autopsy reports, severe pulmonary hemorrhage and hemosiderin deposition in the bilateral lungs and thickening hyaline membrane formation were found, and atelectasis was caused by the small number of alveoli and immature structure. Hyperinflation of the hypoplastic lungs in the ventilation mode of HFOV aggravated the inflammatory response and leads to lung damage. In current neonatal practice, mild ventilation and permissive hypercapnia have become the consensus of ventilator management strategies for neonates with CDH. However, the appropriate adjustment of ventilator parameters cannot be performed with minimal but adequate settings for severe CDH.

4.2 Persistent PH and cardiac dysfunction during fetal-to-neonatal transition in CDH

While the influence factors of PH have been described¹⁵, it remains challenging to pinpoint exactly the factors and at which time point are detrimental in leading to adverse outcome. Elevated right heart pressure, circulatory shunt, hypoventilation, and decreased systemic function, the sequence of physiological process in patients with CDH is complex and varies with the disease severity and progression, which is crucial for guiding treatment to achieve preoperative stabilization and postoperative recovery. In our study, all had been proved severe PH with complete or partial right-to-left shunting across ductus arteriosus, and the ductus arteriosus median size was approximately 4.6 mm at full autopsy, RV volume was enlarged, and the thickness of wall was increased. During fetal cardiopulmonary circulation, pulmonary vascular resistance (PVR) is high and pulmonary blood flow (PBF) is low because the fetal lung is not inflated. Thus, most of right ventricular output is shunted from the ductus arteriosus into the systemic circulation. Left ventricular (LV) preload is derived from the right-to-left shunting of umbilical venous blood flow through the foramen ovale¹⁶. When umbilical cord clamping, as the low-resistance placental vascular bed is removed, loss of umbilical cord venous return reduces LV preload by 30%-50%, and cardiac output decreases when there is an immediate increase in systemic vascular resistance¹⁷. Pulmonary ventilation and vasodilation reduce PVR and increase PBF, triggering a transition from fetal to neonatal circulation. Patients with CDH have lower lung compliance and delayed lung ventilation due to lung hypoplasia, which plus a low cardiac index leading to PH¹⁸. In the process of treatment, lung injury aggravated as well as the degree of respiratory failure, and as hypoxemia and acidosis further stimulate pulmonary vasospasm, PVR persists increased; while the “vicious circle” continued to worsen, the clinical condition deteriorated rapidly. Ultimately, the unstable hemodynamics and rapidity of deterioration of ventilation contribute to the mismatch between oxygen supply and demand. In infants with CDH, PVR is often higher than systemic levels, resulting in extrapulmonary right-to-left shunt and severe hypoxemia. In autopsy cases, the continuous fetal circulation could not be improved with severe PH, thereafter, resulting in more severe right heart failure.

From one of our series, we found the severity of PH and cardiac dysfunction could be unpredictable and disproportionate to respiratory status, whose oxygen saturation remained a high level, however, the patient had severe PDA and died from oliguria. It was also unraveled by Patel ^4,19 et al, holding the view that cardiac dysfunction may be a more important determinant of disease severity than PH. Prolonged left-to-right shunting does not further aggravate pulmonary vasculopathy but is a cause of RV failure²⁰, and the greater part of the literature ignores the role of PDA and RV failure in CDH. The timing of drug or surgical ligation of the ductus arteriosus is less discussed in CDH, which might indicate the future directions for advancement.

4.3 The pathological manifestations and clinical relationship of CDH-related PH are still unclear.

The CDH-related PH is characterized by an interplay of aberrant structural pulmonary development and postnatal pathologic pulmonary vascular remodeling caused by hypoxic pulmonary vasoconstriction²¹. As acknowledged that histological changes in pulmonary arterioles found in animal models and human are the processive proliferation of muscular vascular medial and adventitial layers, decreased vascular branching and vascular reactivity, as well as reduced lumen diameter²², however, we found the observed thickening of the media was in a milder degree than our expectations and the number of muscular arteries observed microscopically wasn’t decreased. Enlargement and congestion of capillaries in the alveolar septum and lung interstitial showed the severity of pulmonary congestion. Among these cases, pulmonary arteries remained the earliest pathobiological feature of vascular remodeling but presented a severe clinical classification. And the effects of pulmonary vasodilators seemed limited. From our experience, we thought the cardio loading conditions might have an important impact on the outcomes of the treatment for PH. The imbalanced of systemic circulation and pulmonary circulation aggravated the clinical course and the hypoxia pulmonary vasoconstriction impacted less. Based on our small observational study, the view needs further in-depth research.

5.CONCLUSION

In conclusion, the pathological changes of CDH can lead to better introspection by the clinical team. In this study, histopathological findings highlighted that ipsilateral pulmonary structure may be normal despite the reduced volume; it was also noteworthy the pulmonary hyaline membrane formation and diffuse hemorrhage indicated unignorable lung damages.

Modern therapy of the respiratory management still should be improved based on lung protection strategies to avoid barotrauma and atelectasis. A vicious circle of lung hypoplasia combined with severe PH and RV failure contributory to refractory hypoxemia are major fatal factors among our series. The management of severe CDH should focus on the timely correction for vicious circle of persistent PH, which is based on the physiological PH in perinatal transition and synergy with giant PDAs; Medications targeted pulmonary vascular lesions strives to transfer to more personalized ways from the single drug-use pattern. Aim to improve oxygenation and minimize cardiopulmonary symptoms, pulmonary vasodilators, gentle ventilation, fluid resuscitation, and hemodynamic homeostasis need mutual coordination. In addition, collecting CDH tissue to establish a biological sample bank, and further translational research can propose new possibilities for clinical treatment.

ACKNOWLEDGMENTS

This study was supported by the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority(XTZD20180305 to Li-Shuang Ma);Foundation project of Beijing Research Association for Chronic Disease Prevention and Health Education in 2022（BJMB0012022028001 to Li-Shuang Ma）

CONFLICT OF INTERESTS

The authors declare that there are no conflicts of interests.

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